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Biomarkers of AKI: Kidney Troponin

Biomarkers of AKI: Kidney Troponin. Kianoush Kashani, MD Assistant Professor in Internal Medicine Consultant Division of Nephrology and Hypertension Consultant Division of Pulmonary and Critical Care Program Director – Critical Care Fellowship

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Biomarkers of AKI: Kidney Troponin

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  1. Biomarkers of AKI:Kidney Troponin Kianoush Kashani, MD Assistant Professor in Internal Medicine Consultant Division of Nephrology and Hypertension Consultant Division of Pulmonary and Critical Care Program Director – Critical Care Fellowship Mayo Clinic Multidisciplinary Simulation Center (MCMSC) kashani.kianoush@mayo.edu

  2. Therapeutic Window Volume ResponsiveAKI Volume UnresponsiveAKI High Risk Hypervolemia Euvolemia Hypovolemia Therapeutic Window Biomarkers Sensitive Traditional Mortality Kidney Function Himmelfarb et al: Clin J Am Soc Nephrol 3:962, 2008

  3. Kidney Troponin Period ACS AKI 1960s LDH Serum creatinine 1970s CPK, myoglobin Serum creatinine 1980s CK-MB Serum creatinine 1990s Troponin T Serum creatinine 2000s Troponin I Serum creatinine • Developed multiple therapies •  mortality • Supportive therapy • High mortality

  4. Serum and urinary cystatin C 13KDa protein Synthesized and released into plasma by all nucleated cells Still dependent on lean body mass (MacDonald, AJKD, 48(5) 712-719, 2006) Serum cystatin C freely filtered (small and non-ionic) More sensitive than Scr as marker of GFR Cystatin C catabolized in PT Tubular damage  appearance in urine Won K et al, Curr Opin Crit Care, 10:476-482, 2004

  5. Cystatin C Male Non-Hispanic White Obesity and Waste circumference Cystatin C Hyperthyroid Glucocorticoid use Increased CRP Smoker Madero, et al; CO Neph HTN. 18:258–263. 2009

  6. Cystatin C and mortality N = 845 ICU patients Based on RIFLE criteria 271  AKI; 562  non-AKI Cystatin C and mortality related in both cohorts Stronger in patients without AKI Bell et al. Nephrol Dial Transplant (2009) 1 of 7

  7. Cystatin C and mortality Bell et al. Nephrol Dial Transplant (2009) 1 of 7

  8. Neutrophil Gelatinase-Associated Lipocalin (NGAL) Lipocalin superfamily Markedly up-regulated in early post-ischemic kidney in proliferating PT cells NGAL in plasma and urine Marker of AKI Appears in urine within 3 hours of ischemic injury and cisplatin exposure Won K: Curr Opin Crit Care 10:476, 2004 Mishra J et al: JASN 14:534, 2003

  9. NGAL 2-3 Hours After CPB as the Predictor of AKI AKI definition Timing of NGAL AUC-ROC to Patients Creatinine Timing of postop measurement predict AKIReference (no.) Setting increase creatinine increase (after end of CPB) (plasma/urine) Mishra et al 71 Paediatric >50% Within 5 days At 2 h 0.91/0.99 Dent et al 120 Paediatric >50% Within 5 days At 2 h 0.96/– Bennett et al 196 Paediatric >50% Within 5 days At 2 h –/0.95 Wagener et al 81 Adult >50% Within 5 days At 3 h –/0.74 Wagener et al 426 Adult >50% or Within 2 days At 3 h –/0.60 >0.3 mg/dL Koyner et al 72 Adult >25% or need Within 3 days At ~2 h* 0.53/0.70 for RRT Haase-Fielitz et al 100 Adult >50% Within 5 days At ~2 h* 0.80/– Haase-Fielitz et al: NDT, May 27, 2009

  10. NGAL and Cystatin C after CPB Haase et al; Ann Thorac Surg 2009;88:124 –30. 2009

  11. NGAL predictive value Nickolas et al; Ann Intern Med. 2008;148:810-819

  12. Angiopoietin 2:A prognostic marker? Angiopoietin-2 (Ang-2) Circulating antagonistic ligand of the endothelial-specific Tie2 receptor Increases capillary leak Is not removed during dialysis n= 117 AKI at the time of initiation of RRT Circulating Ang-2 correlated with: Impaired oxygenation low mean arterial pressure vasopressor dose SOFA score Ang-2 significantly higher in non-survivors at day 0 and day 14 after initiation of RRT Kumpers et al. Intensive Care Med (2010) 36:462–470

  13. Angiopoietin 2:A prognostic marker?

  14. Kidney injury molecule-1(KIM-1) Transmembrane protein Not detectable in normal kidney tissue Very high in dedifferentiated PT cells after ischemic or toxic injury Protein and mRNA up-regulated in 48-hr post ischemic Won et al, KI, 62: 237-244, 2002

  15. Rena-Stick Human Rena-Stick Vaidya et al, Kidney International (2009) 76, 108–114

  16. Multi-bead assay Vaidya et al, 2008 Clin. Trans Sci.

  17. Urinary and Serum Biomarkers for the Diagnosis Of AKI: An In-depth Review of the Literature Vanmassenhove et al. Nephrol Dial Transplant (2012) 0: 1–20

  18. Discovery Cohort in Search forNew Kidney Troponins

  19. Vienna Cohort Age 18 ICU + sepsis n=134 Duke Cohort Age 18 At least 1 risk factor n=123 Mayo Cohort Age 18 At least 1 risk factor n=265 Pilotstudies Discovery Best 2 markers Sapphire Study 35 sites(20 North American, 15 Europe) Age >21, critically ill3,no AKI (stage 2 or 3)4n=744 16 patients excluded(2 withdrew consent,7 lost to follow-up,7 with invalid or missing test results) Validation n=7285 Within12 hr No AKI n=416 No stage 1 n=211 No stage 2 n=83 AKI stage 3 n=18

  20. ROC-AUC – Comparison of Novel Markers [TIMP-2]  [IGFBP7] Urine TIMP-2 Urine IGFBP7 Urine NGAL Serum creatinine Plasma NGAL Plasma cystatin C 0.4 0.5 0.6 0.7 0.8 0.9 AUC (with 95% CI)

  21. Sapphire Trial

  22. Vienna Cohort Age 18 ICU + sepsis n=134 Duke Cohort Age 18 At least 1 risk factor1 n=123 Mayo Cohort Age 18 At least 1 risk factor2 n=265 Discovery Best 2 markers Sapphire Study 35 sites(20 North American, 15 Europe) Age >21, critically ill,no AKI (stage 2 or 3)n=744 SapphireTrial 16 patients excluded(2 withdrew consent,7 lost to follow-up,7 with invalid or missing test results) Validation n=728 Within12 hr No AKI n=416 AKI stage 1 n=211 AKI stage 2 n=83 AKI stage 3 n=18

  23. Urine KIM-1Sapphire Study Concentration (ng/mL) Sepsis RIFLE R RIFLE I RIFLE F COPD Diabetes CHF CAD CKD Surgery Respiratory No RIFLE Emphysema Cardiovascular Cerebrovascular Respiratory other Chronic bronchitis ICU admission Subjects without AKI AKI subjects stratified by RIFLE

  24. Urine NGALSapphire Study Concentration (ng/mL) Sepsis RIFLE R RIFLE I RIFLE F COPD Diabetes CHF CAD CKD Surgery Respiratory No RIFLE Emphysema Cardiovascular Cerebrovascular Respiratory other Chronic bronchitis ICU admission Subjects without AKI AKI subjects stratified by RIFLE

  25. Sapphire Study [TIMP2][IGFBP7] Sepsis RIFLE R RIFLE I RIFLE F COPD Diabetes CHF CAD CKD Surgery Respiratory No RIFLE Emphysema Cardiovascular Cerebrovascular Respiratory other Chronic bronchitis ICU admission Subjects without AKI AKI subjects stratified by RIFLE

  26. Sapphire Study P<0.00003 Relative risk of RIFLE-I/F P=0.00008

  27. MAKE30 Sensitivitythreshold0.3 Risk for AKI (KDIGO stage 2-3) • Composite score • Major adverse kidney events truncated in 30 days • Death • Need for RRT • Double Scr at 30 day or d/c Specificitythreshold2 Risk of MAKE30 [TIMP2][IGFBP7] ((ng/mL)2/1000)

  28. Kidney Troponin:where are we? Period ACS AKI 1960s LDH Serum creatinine 1970s CPK, myoglobin Serum creatinine 1980s CK-MB Serum creatinine 1990s Troponin T Serum creatinine 2000s Troponin I Serum creatinine

  29. شكراً “The best interest of the patient is the only interest to be considered”

  30. Questions & Discussion

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